Incorporation of positron emitting fluorine-18 (half-life=110 min) into aromatic ring systems plays a very important role in the development of novel biomarkers for utilization in Positron Emission Tomography (PET). Two major pathways are commonly used for this process, namely electrophilic and nucleophilic fluorine substitution reactions. Electrophilic fluorination reactions can only provide products with low specific activities (ca 1-5 Ci/mmol) because of the unavoidable addition of non-radioactive elemental fluorine (often called carrier fluorine) during the current production techniques for F-18 labeled fluorine. The combination of labeled fluorine and carrier fluorine is referred to as [18F] F2. A typical example of electrophilic radiofluorination can be summarized by the following reaction:
                Where R=electron withdrawing groups (e.g. CHO, COOEt, CN, NO2 etc) or electron donating groups (e.g. CH3, OCH3 etc)        
Low specific activity biomarkers prepared by electrophilic aromatic radiofluorination reactions with [F-18]fluorine and reagents derived from it are generally useful for monitoring enzyme-mediated processes (e.g., aromatic amino acid decarboxylase dependent transformation). However, they are unsuitable for investigation of biochemical processes such as receptor systems or enzyme inhibition.
Nucleophilic fluorination of aromatic rings, on the other hand, provides products with high specific activity (ca 1,000-10,000 Ci/mmol). High specific activity [F-18]fluoride ion, the fluorinating agent for nucleophilic substitution reactions, is more conveniently prepared in large quantities (1-10 Ci) unlike molecular [F-18]fluorine which is obtained in 0.3-0.7 Ci levels. Facile displacement of certain leaving groups (e.g. nitro and quaternary ammonium moiety) in aromatic systems activated by electron withdrawing substituents (e.g. CHO, COCH3, NO2, CN, COOCH3) by high specific activity [F-18]fluoride ion is well documented and can be depicted as follows:
                Where R=electron withdrawing groups (e.g. CHO, COOEt, CN, NO2 etc) located at ortho or para position with respect to the group X, and X═NO2 or⊕ N(CH3)3         
Simple deactivated aromatic rings such as the example cited above provide [F-18]fluorinated products in good radiochemical yields (30-80%). However, as the complexity of the aromatic ring system increases (which is the case with almost all the useful biomarkers) the radiochemical yields obtained by this reaction drops drastically. Further, aromatic compounds lacking electron withdrawing/deactivating substituents (i.e. CHO, CN, NO2 etc) fail to undergo this reaction. Two different routes have been formulated for aromatic nucleophilic fluorination reactions for rings that carry no deactivating substituents (e.g. CHO, NO2, CN etc) or carry groups that are electron donating in nature (e.g. CH3, OCH3). The following reactions have been identified for aromatic nucleophilic substitution reactions for phenyl rings that bear electron-donating groups:
                Where R=electron donating groups (e.g. CH3, OCH3 etc) located at ortho, meta and para positions with respect to the triazene group.        
                Where R=electron donating groups (e.g. CH3, OCH3 etc) located at ortho, meta and para positions with respect to the iodonium group.        
The radiochemical yields obtained for the fluorinated products by the above two reactions are generally less then 60% with simple molecules and they generally both fail to be useful for certain complex systems.
Thus, there is a great need for fluorination reactions and particularly for nucleophilic aromatic fluorination reaction conditions that are suitable for the preparation of F-18 labeled biomarkers having a variety of substituents, including electron donating groups. Use of such reactions will make many different biomarkers easily accessible and will facilitate development and utilization of novel molecular imaging probes in PET. It is also anticipated that similar reactions with various nucleophiles would expand the utility of the approach to a multitude of labeled and unlabeled molecules.